Dual antiplatelet therapy with aspirin and clopidogrel is used in patients with acute coronary syndrome (ACS), owing in part to an increased incidence of thrombogenesis. This therapy has been proved to be beneficial both with and without percutaneous coronary intervention (PCI),1–3 and is endorsed by numerous clinical management guidelines.4–9 However, clinical application of clopidogrel is hampered by its pharmacodynamic characteristics because its biotransformation into active metabolites results in a slow onset of action, and a variable response10,11 with a potentially increased risk of stent thrombosis and myocardial infarction (MI).12 The argument that clopidogrel treatment in Asian patients may not be as effective as that in Caucasian patients is ongoing, based on the observation that the frequency of the cytochrome P450 2C19 loss-of-function allele accompanied by high platelet reactivity is more prevalent in the Asian population.13
Ticagrelor, a novel oral P2Y12 antagonist that does not undergo biotransformation to active metabolites, has many favorable pharmacodynamic characteristics, including rapid onset of action and being reversible, and consistent inhibition of platelet function.14,15 In the Platelet Inhibition and Patient Outcomes (PLATO) study, compared with the treatment with a therapeutic dose of 75 mg/d clopidogrel, treatment with 90 mg ticagrelor twice daily significantly reduced the rate of death from vascular causes, MI, and stroke without increasing the overall major bleeding, but with an increase in non-procedure-related bleeding in ACS patients with or without ST-segment elevation.15 Therefore, certain clinical management guidelines recommend ticagrelor over clopidogrel for P2Y12 inhibition in patients with ACS.5,7–9
Recently, the possibility of a paradox with regard to antiplatelet treatment in the East Asian population has been reported.16,17 Some studies have shown a higher prevalence of on-treatment platelet reactivity, but with a similar thrombotic event rate after PCI in East Asian patients compared with Caucasian patients.16,17 In contrast to ischemic events, the risk of serious bleeding in the East Asian population appears to be greater than that in the Caucasian population.16,17 Therefore, the superior efficacy and acceptable safety profile of ticagrelor to that of clopidogrel, as demonstrated in the PLATO trial, may not be reproducible in an East Asian population, particularly a Chinese population. A recently published study that enrolled 801 East Asian individuals (90% of whom were Japanese) showed that the incidence of composite primary endpoints and PLATO-defined major bleeding tended to be higher in ACS patients treated with ticagrelor than in those treated with clopidogrel.18 Based on clinical experience and evidence with anticoagulants, the expected responses of Japanese and Chinese patients to antithrombotic treatments may not be similar.19,20 To the best of our knowledge, no previous studies have investigated the efficacy and safety of ticagrelor compared with clopidogrel in an Asian population in real-life situations. Therefore, the present Efficacy and Safety of Ticagrelor versus Clopidogrel in Acute Coronary Syndrome in Taiwanese (ESTATE) study aimed to determine whether ticagrelor is superior to clopidogrel for the prevention of vascular events and death in Taiwanese patients with ACS.
2.1. Study population
Eligible patients were consecutively enrolled in this multicenter, retrospective study. The study protocol did not require informed consent and was approved by the Institutional Review Board of the National Cheng Kung University Hospital, Tainan, Taiwan (identifier: NCKUH B-ER-104-112) and Tainan Municipal Hospital, Tainan, Taiwan (identifier: SCMH 1040801). In order to make a parallel comparison of ticagrelor versus clopidogrel during the same study period, we screened eligible patients from July 2013 in the Tainan Municipal Hospital and from June 2014 in the National Cheng Kung University Hospital until February 2015. Ticagrelor had been listed and available in both of these hospitals since the given dates. The eligible patients were selected according to the following screening criteria: (1) selection of patients with discharge codes 410.xx and 411.xx, using ICD-9 version; (2) limiting the patient population to those with primary or secondary discharge diagnosis of ACS, including acute ST-segment-elevation MI (STEMI), non-ST-segment-elevation MI (NSTEMI), unstable angina, and undifferentiated ACS (including undetermined MI, apical ballooning syndrome, coronary spasm with elevated cardiac-specific enzymes, and typical ST-segment deviation in electrocardiography); (3) including only those patients who were taking ticagrelor or clopidogrel on or before discharge; and (4) limiting the number of patients hospitalized via the emergency department with an initial manifestation of ACS, symptom onset <24 hours, and duration of symptoms ≥10 minutes at rest. Patients were categorized into two groups based on drug administration at admission: ticagrelor (n = 324) and clopidogrel (n = 604). The clinical and endpoint data were collected and recorded by a medical chart review if patients were regularly followed up in our hospital; however, telephone calls or direct contact with the participants or their families was made for patients without regular medical follow-up. However, the authors received the data in an anonymous manner with no direct reference to medical charts and no direct contact with participants or their families.
2.2. Outcome measurement
The minimum follow-up period was 1 month and the maximum 1 year. We performed a prespecified analysis of the primary PLATO composite efficacy endpoints (death from vascular causes, MI, or stroke).21 Secondary endpoints included individual occurrence of components of the primary PLATO efficacy endpoints. Additional efficacy endpoints included stent thrombosis, among others.
The primary ESTATE composite safety endpoint was timed to the first PLATO-defined and PLATO-adjudicated major bleeding event.21 Occurrences of major, minor, and minimal bleeding, as well as all bleeding (combined major, minor, and minimal bleeding) and combined major and minor bleeding events were recorded and compared between groups, as per a study design similar to that used for PLATO.21
2.3. Definitions of endpoints
Death from vascular causes was defined as death from cardiovascular or cerebrovascular causes, including deaths due to an unknown cause. MI was defined in accordance with the universal definition proposed in 2012.22 Stent thrombosis was evaluated according to the Academic Research Consortium criteria.23 Stroke was defined as the focal loss of neurologic function caused by an ischemic or a hemorrhagic event with residual symptoms lasting at least 24 hours or eventually leading to death.
2.4. Statistical analyses
All variables were presented as mean ± standard deviation and skewed data were reported as the median (interquartile range). Chi-square or Fisher's exact tests were used for comparison of categorical variables between groups, while the Mann–Whitney U test or unpaired Student t test was used for continuous variables, as appropriate. If more than one endpoint occurred within the follow-up period, only the first event was considered. Kaplan–Meier analysis was used to assess patient survival and event-free status, using the log-rank test (Cox–Mantel) to ascertain differences between groups. To identify the independently predicted role of ticagrelor use for the occurrence of primary efficacy endpoint, it was adjusted with variables only mismatched in propensity score matching cohort using a multivariate Cox proportional-hazard model using a backward (likelihood ratio) method for stepwise selection of independent covariates. A p value <0.05 was considered statistically significant.
As a result of the nonrandomized nature of this study, propensity score analysis was performed in order to minimize selection bias resulting from differences in clinical characteristics between the groups. The propensity score for the likelihood of receiving ticagrelor or clopidogrel was computed using multivariate logistic regression analysis, conditional on covariates such as age, sex, body weight, smoking status, ACS spectrum, and the presence of cardiovascular diseases, diabetes mellitus, and chronic kidney disease. Then, using the Greedy 5 → 1 digit match technique, the propensity score was used to match ticagrelor or clopidogrel patients in a 1:1 ratio. The kernel densities before and after matching are shown in Fig. S1. A sensitivity analysis was conducted across various subgroups to test the robustness of our findings, including groups classified by sex, age, body weight, hospital type, and the presence of diabetes mellitus, hyperlipidemia, and chronic kidney disease. Propensity score matching and subgroup analysis were performed using SAS software (version 9.1.3; SAS Institute Inc., Cary, NC, USA). Additional statistical analyses were performed using SPSS for Windows (version 13.0; SPSS Inc., Chicago, IL, USA).
3.1. Baseline characteristics between groups
A total of 828 patients with ACS were included in this study. Significant differences were observed between the two groups for certain baseline characteristics and parameters (Table 1). Patients assigned to the ticagrelor group were significantly younger and had a significantly lower prevalence of diabetes mellitus, hypertension, hyperlipidemia, peripheral artery disease, congestive heart failure, end-stage renal disease, and previous PCI or bypass surgery. However, a higher number of patients in this group had a habit of tobacco smoking. While body weight was significantly different between the two groups, body mass index was well matched. In the ticagrelor group, patients had a lower Thrombolysis in Myocardial Infarction (TIMI) risk score and a higher percentage of low-risk Killip classification, but higher peak levels of cardiac enzymes and inflammation markers such as white blood cell and platelet counts, attributable to an increased incidence of MI.
After propensity score matching, 448 patients were selected and divided into two equal groups. Baseline characteristics were well matched, with the exception of a higher percentage of patients with end-stage renal disease and lower hemoglobin levels in the clopidogrel group.
3.2. Drug treatment parameters and invasive procedures
Comparisons of parameters regarding drug treatment and invasive procedures between the two groups are presented in Table 2. Prior to propensity score matching in the ticagrelor group, fewer patients were treated with an angiotensin-receptor blocker, a calcium-channel blocker, nicorandil, nitrate, or an H2-histamine inhibitor, whereas more patients were undergoing P2Y12 antagonist switch therapy during hospitalization or discharge. Nevertheless, total exposure time and adherence rate of the main P2Y12 antagonist were similar between the two groups. A higher number of patients underwent invasive diagnostic and therapeutic procedures in the ticagrelor group. However, fewer patients in this group received drug-eluting stent deployment.
After propensity score matching, parameters regarding drug treatment and invasive procedures received were well matched, with the exception of an increased number of patients in the ticagrelor group who were on statin treatment, undergoing P2Y12 antagonist switch therapy, and receiving coronary angiography or PCI.
3.3. Clinical outcomes follow-up
The mean follow-up period was 164.3 ± 116.4 days. Table 3 shows that compared with the clopidogrel group, ticagrelor treatment did not significantly influence the primary PLATO efficacy endpoint, whereas it significantly increased total mortality (11.4% vs. 7.0%, p = 0.02) with a lower incidence of stroke (0.9% vs. 2.8%, p = 0.06) in the overall cohort. However, after propensity score matching, patients in the ticagrelor group had a lower incidence of the primary PLATO efficacy endpoint (hazard ratio: 0.56; 95% confidence interval: 0.30–1.04; p = 0.07) and stroke (hazard ratio: 0.15; 95% confidence interval: 0.02–1.24; p = 0.08) with marginal statistical significance (Table 3 and Fig. 1). There was no significant difference in the incidence of vascular death, MI, total death, or stent thrombosis between the two groups. In the propensity matching cohort, a subgroup analysis and evaluation of seven clinical variables to determine the effect of ticagrelor versus clopidogrel on the occurrence of the primary PLATO efficacy endpoint showed that a protective effect in favor of ticagrelor treatment was consistent across all subgroups (Fig. 2).
There was no significant difference in the incidence of primary safety endpoint, fatal bleeding, or intracranial hemorrhage between the two groups in either the overall or the propensity-matched cohort (Table 4). However, ticagrelor treatment caused a higher rate of minor, minimal, or all bleeding before matching (Table 4). In the propensity-matched cohort, there was no significantly different rate of bleeding, including minor, minimal, and all bleeding (6.3% vs. 3.1%, p = 0.12; 10.3% vs. 6.7%, p = 0.18; 19.6% vs. 14.3%, p = 0.13, respectively), between both groups.
The most common bleeding site was in the upper gastrointestinal tract in both overall and propensity-matched cohorts, regardless of whether patients were treated with ticagrelor or clopidogrel (Table 4). Ecchymosis on the skin was observed with ticagrelor treatment, and an unknown bleeding site in the gastrointestinal tract was observed with clopidogrel treatment.
A higher number of patients treated with ticagrelor experienced dyspnea as compared with those treated with clopidogrel in both overall (25.0% vs. 14.6%, p < 0.001) and propensity-matched (21.0% vs. 11.6%, p = 0.01) cohorts (Table 4). Furthermore, the incidence of dyspnea-related discontinuation of P2Y12 antagonist treatment tended to be higher in the ticagrelor group by propensity score matching.
Interestingly, a significantly higher number of patients underwent drug switching or discontinuation during P2Y12 antagonist treatment in the ticagrelor group in both overall (21.6% vs. 15.6%, p = 0.02) and propensity-matched (16.5% vs. 4.5%, p < 0.001) cohorts (Table 4). The most common cause of drug switching or discontinuation was bleeding in the ticagrelor group and an unknown cause in the clopidogrel group (Table 4).
3.4. Independent predictors of the primary PLATO efficacy endpoint
By univariate analysis, 15 univariables (p < 0.1), including ticagrelor use, were associated with the occurrence of the primary endpoint. To identify independent predictors of the primary PLATO efficacy endpoint and to avoid overadjustment and collinearity, owing to the low incidence of total primary events, ticagrelor use was adjusted with end-stage renal disease and statin use only because they were mismatched in the propensity score matching cohort and showed statistical insignificance in multivariate analysis (Table 5). To exclude the potential impact of end-stage renal disease on the clinical outcome, we repeated analysis in 406 patients without any history of end-stage renal disease and found that ticagrelor still has a marginally protective effect on the occurrence of the primary endpoint (Table S1).
The current study is the first of its kind that investigated the efficacy and safety of ticagrelor versus clopidogrel in patients with ACS in Asia (including Taiwan) in a real-life clinical setting. Our data show that ticagrelor treatment has a marginally favorable effect on the occurrence of the composite outcome, including MI, stroke, or vascular death, with a similar incidence of major bleeding or other bleeding at the expense of a significantly higher incidence of dyspnea.
According to our results in the overall cohort, we can appreciate the prescription behavior for P2Y12 antagonists in a real-world setting. Physicians in this region prefer ticagrelor for the treatment of ACS patients with MI (STEMI or NSTEMI) owing to a lower baseline cardiovascular risk as well as a lower bleeding risk. This is partly attributable to awareness of the pharmacodynamics, clinical efficacy, and safety outcomes from previous trials. Previous studies have shown that cardiac enzymes and inflammatory biomarkers are significantly higher in patients with MI.24,25 Therefore, in the present study, peak levels of cardiac enzymes after ACS and inflammatory biomarkers at baseline were much higher in patients treated with ticagrelor. In Taiwan,26 primary PCI and early invasive strategies are the main management approaches for STEMI and NSTEMI, respectively. In this region, STEMI patients receive bare-metal stent deployment more frequently than patients with other coronary artery diseases.26 Therefore, from our perspective, it is easy to understand why a higher number of invasive diagnostic and interventional procedures with bare-metal stent deployment are performed in the ticagrelor group. However, it is not clear as to why fewer patients in the ticagrelor group received guideline-directed medial therapy, and we can only speculate that this could be attributable to selection bias.
In the overall cohort, there were markedly heterogeneous background characteristics, diverse medications, and treatment procedures between the groups; this probably confounded the comparison of the efficacy and safety effects. Using propensity score matching, our data appear to be in agreement with those of the PLATO trial15 and support the notion that ticagrelor might be more effective than clopidogrel in patients with ACS, but can induce more minor/minimal bleeding than clopidogrel. The occurrence of the primary efficacy endpoint was similar in the clopidogrel groups in the ESTATE and PLATO trials (11.6% vs. 11.7%).15 When compared with the PLATO trial,15 a relative risk reduction was observed with ticagrelor regarding the occurrence of primary efficacy endpoint (34% vs. 16%) in the ESTATE study, although not statistically significant. Furthermore, ticagrelor treatment showed a tendency to reduce the incidence of stroke in the ESTATE study, while this was not observed in the PLATO trials. However, an insignificant 47% increase in the relative risk of primary efficacy endpoint was observed in the PHILO study, of which 90% of enrolled patients were Japanese.18 When all the above results are taken together, the effect of ticagrelor probably differs across Chinese, Japanese, and Caucasian patient populations.
The incidence of all bleeding (major or minor bleeding) was significantly higher with ticagrelor treatment in the PLATO and PHILO trials (16.1% vs. 14.6% and 23.8% vs. 14.7%, respectively), but not in the current ESTATE trial (10.3% vs. 8.9%). The lower bleeding rate observed in the present study could be attributable to missing information or incomplete patient records, as well as the shorter follow-up period and retrospective nature of the study. However, in actuality, a real-world observational study enrolls a higher number of high-risk and frail patients who are generally excluded from prospective, randomized controlled trials. Even so, the bleeding rates in the present study, including minimal bleeding, are not high. Therefore, the hypothesis that a higher bleeding risk is associated with antiplatelet treatment in the East Asian population should be re-evaluated for the Chinese population. Indeed, variation in the drug response of the East Asian population remains controversial. Based on clinical experience and evidence with anticoagulants, response to antithrombotic treatments may be dissimilar between the Japanese and Chinese populations.19,20 Furthermore, the beneficial effect of pitavastatin on the metabolic profile of Japanese patients27 could not be reproducible in either Korean28 or Taiwanese patients.29
In addition to bleeding, a major adverse effect demanding attention is dyspnea. The reported incidence of dyspnea with ticagrelor treatment is around 13.8–38.6%.15,30,31 In contrast with the very low rate of dyspnea observed in the PHILO study,18 dyspnea was seen in 21% of the patients treated with ticagrelor in the ESTATE study; this percentage is very similar to that in a previous registry study.31 When compared with clopidogrel treatment, ticagrelor causes a four-fold increase in the incidence of dyspnea and required discontinuation of a P2Y12 antagonist in the present study. The percentage of affected patients observed in this study is much higher than that of the PLATO trial; however, the clinical judgment and discretion of a physician in a real-world setting must be recognized as a contributing factor, as this certainly differs from that of randomized controlled trials.
This study had several limitations, including a small sample size as well as subdivision of patients into groups according to propensity score matching. These limitations decreased the statistical power of our analyses. As a result of the retrospective design of this study, potential reverse causality could not be excluded, although multivariate adjustment and propensity score matching were performed. Finally, we could not exclude the possibility of selection bias, potential missing information, and incomplete patient records.
In conclusion, to the best our knowledge, this is the first study to evaluate the efficacy and safety of ticagrelor versus clopidogrel in Asian patients with ACS in a real-world setting. Ticagrelor treatment could have a marginally favorable effect on the occurrence of MI, stroke, or vascular death at the expense of a higher risk of dyspnea. The hypothesis regarding higher bleeding risk with antiplatelet treatment in an East Asian population warrants further evaluation in the Chinese population. This pilot study provides a scientific base to call for a larger, suitably powered Phase 4 prospective or observational study in this ethnic population.
This work was supported, in part, by the Tainan Municipal Hospital Research Grant (RA14005), the Multidisciplinary Center of Excellence for Clinical Trial and Research (grant number DOH 102-TD-B-111-002) from the Department of Health, Executive Yuan, Taiwan; a Landmark Project to Promote Innovation and Competitiveness of Clinical Trials by the Excellent Clinical Trial and Research Center in National Cheng Kung University Hospital from the Ministry of Health and Welfare, Taiwan (MOHW103-TDU-B-211-113002 and MOHW104-TDU-B-211-113002); and the Ministry of Science and Technology, Taiwan (grant number MOST 104-2314-B-006-085). The funding organizations did not have a role in the design, conduct, or analysis of this study.
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Appendix A Supplementary data
The following are the supplementary data related to this article:
Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.jcma.2016.02.010.
ESTATE Investigators: Cheng-Han Lee, Ting-Hsing Chao, Chih-Chan Lin, Yi-Heng Li, Ju-Yi Chen, Ping-Yen Liu, Shih-Hung Chan, Wen-Huang Lee, Po-Tseng Lee, Liang-Miin Tsai, Wei-Chuan Tsai, and Li-Jen Lin from Division of Cardiology, Department of Internal Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan; Ching-Lan Cheng from Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan, R.O.C.; and I-Chih Chen, Ching-Chang Fang, Yi Chen, Ching-Lung Yu, and Chun-Yuan Lin from Division of Cardiology, Department of Internal Medicine, Tainan Municipal Hospital, Tainan, Taiwan.